Categories: Health-Medical

Therapeutic Starvation And Autophagy In Prostate Cancer: A New Paradigm For Targeting Metabolism In Cancer Therapy

In the online edition of The Prostate, Robert S. DiPaola and co-investigators reported their research on autophagy. Autophagy is a mechanism of cellular resistance or alternatively cell death. Cancer metabolism differs from normal cells in that it uses anaerobic glycolysis as opposed to oxidative phosphorylation to metabolize glucose. With nutrient deprivation, a cell response to starvation occurs whereby cellular organelles and bulk cytoplasm are targeted to lysosomes for degradation to supply an alternate energy source. Sustained autophagy under conditions of protracted cellular starvation is proposed to lead to cell death, thereby the survival or death consequences of autophagy are condition-dependent. Autophagy is proposed to be impaired in prostate cancer (CaP) due to activation of mTOR, which inhibits autophagy or through allelic loss of the essential autophagy gene beclin1. In this research, the effect of a prototypical inhibitor of glycolysis, 2DG, a glucose analogue that inhibits glucose uptake was assessed to determine if 2DG induces cytotoxicity and autophagy in CaP cells.

LNCaP and PC3 cells were treated with increasing concentrations of 2DG and their growth was inhibited in a dose dependent fashion. Using time-lapse microscopy, growth was decreased more by therapeutic starvation over time. Markers of cell cycle checkpoint proteins were decreased, thus supporting these observations. Expression of the fluorescent autophagy marker GFP-LC3 in the LNCaP and PC3 cells was performed with or without modulation of the expression of the autophagy regulator Beclin1 using siRNA. 2DG induced Beclin1 dependent autophagy in both cell lines, and knockdown of beclin1 abrogated 2DG-induced autophagy. To determine the effect of Beclin1 on apoptotic proteins such as caspase-3, the effect of 2DG on the cleaved (activated) fragment of caspase-3 was assessed. Caspase-3 was cleaved to the active fragment in cells treated with 2DG. Addition of Beclin1 siRNA, which abrogates autophagy, permitted increased activation of caspase-3 at lower 2DG concentrations. This suggests that under these conditions, Beclin1 and autophagy were associated with resistance to apoptosis. These data suggest autophagy is a mechanism of resistance to 2DG-induced cytotoxicity.

The researchers also developed a tissue microarray system to assess Beclin1 using digitized image analysis. This system permits more standardized assessment of autophagy in tissue samples and for example, may prove useful in clinical trials of agents that target glycolysis to induce cytotoxicity.

Radhe

Share
Published by
Radhe

Recent Posts

Basics of Monthly Menstrual Cycle

The menstrual cycle is considered a normal part of a woman’s life. It’s a reproductive…

2 weeks ago

The First Year Vaccine Schedule for Babies in India

Children's immune systems are weak due to their young age, rendering them susceptible to viral…

1 month ago

Precautions you Need to Remember During IVF Pregnancy

To be able to conceive naturally is God’s greatest gift to women. Pregnancy is one…

1 month ago

Tummy Tuck Surgery: Benefits, Preparations, Risks & More

Do sit-ups not give you the flat stomach you desire? You might be thinking of…

1 month ago

Is the period still taboo?

According to many people, a woman's menstrual cycle is considered taboo. In earlier days, women…

2 months ago

Exercise And Diet A Couple Should Follow During IVF

To have thought of IVF, you must have gone through all the other options. Now…

2 months ago

This website uses cookies.